Substituted tetrahydrofurans as modulators of sodium channels

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

What is claimed is: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X 2a  is N or N + —O − ; 
 X 4a  is C—R 4a ; 
 X 5a  is N or N + —O − ; 
 X 6a  is C—R 6a ; 
 each R is independently H or C 1 -C 6  alkyl; 
 R 4a  and R 6a  are each independently H, halo, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 4b1  and R 4b2  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or C 1 -C 6  haloalkyl; 
 R 5b1  and R 5b2  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or C 1 -C 6  haloalkyl; 
 X 3c  is N or C—R 3c ; 
 X 4c  is N or C—R 4c ; 
 X 5c  is N or C—R 5c ; 
 X 6c  is N or C—R 6c ; 
 R 2c  is H, OH, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, or -L 1 -L 2 -(C 3 -C 6  cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo; 
 L 1  is a bond or O; 
 L 2  is a bond or C 1 -C 6  alkylene; 
 R 3c  is H, halo, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 4c  is H, halo, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 5c  is H, halo, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; and 
 R 6c  is H, halo, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 and 
 provided that no more than one of X 3c , X 4c , X 5c , and X 6c  are N. 
 
       
     
     
       2. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 4b1  and R 4b2  are each independently H, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 5b1  and R 5b2  are each independently H, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 X 3c  is C—R 3c ; 
 X 4c  is C—R 4c ; 
 X 5c  is C—R 5c ; 
 X 6c  is C—R 6c ; and 
 R 2c  is H, OH, halo, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, or C 1 -C 6  haloalkoxy. 
 
     
     
       3. The compound of  claim 1 , wherein the compound has formula (I-A) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       4. The compound of  claim 1 , wherein the compound has formula (I-B) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       5. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 
       
         
           
           
               
               
           
         
         6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyrazine-2-carboxamide, 
         6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, 
         6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide, and 
         6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide. 
       
     
     
       6. A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles. 
     
     
       7. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 7 , wherein the voltage-gated sodium channel is Na V 1.8. 
     
     
       9. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       10. The method of  claim 9 , where the method comprises treating or lessening the severity in the subject of neuropathic pain. 
     
     
       11. The method of  claim 10 , wherein the neuropathic pain comprises post-herpetic neuralgia. 
     
     
       12. The method of  claim 10 , wherein the neuropathic pain comprises small fiber neuropathy or idiopathic small-fiber neuropathy. 
     
     
       13. The method of  claim 10 , wherein the neuropathic pain comprises diabetic neuropathy. 
     
     
       14. The method of  claim 9 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain. 
     
     
       15. The method of  claim 14 , wherein the musculoskeletal pain comprises osteoarthritis pain. 
     
     
       16. The method of  claim 9 , wherein the method comprises treating or lessening the severity in the subject of acute pain. 
     
     
       17. The method of  claim 16 , wherein the acute pain comprises acute post-operative pain. 
     
     
       18. The method of  claim 9 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain. 
     
     
       19. The method of  claim 18 , wherein the postsurgical pain comprises bunionectomy pain. 
     
     
       20. The method of  claim 18 , wherein the postsurgical pain comprises herniorrhaphy pain. 
     
     
       21. The method of  claim 18 , wherein the postsurgical pain comprises abdominoplasty pain. 
     
     
       22. The method of  claim 9 , wherein the method comprises treating or lessening the severity in the subject of visceral pain. 
     
     
       23. A method of treating or lessening the severity in a subject of pain comprising administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       24. The method of  claim 9 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, or a pharmaceutically acceptable salt thereof.